Rheumatology for the Internist 2017 Dr. Mark Matsos Associate Professor of Medicine Division of Rheumatology McMaster University

Transcription

1 Canadian Society of Internal Medicine Annual Meeting 2017 Toronto, ON Rheumatology for the Internist 2017 Dr. Mark Matsos Associate Professor of Medicine Division of Rheumatology McMaster University

2 CSIM Annual Meeting 2017 The following presentation represents the views of the speaker at the time of the presentation. This information is meant for educational purposes, and should not replace other sources of information or your medical judgment. Learning Objectives: Describe new developments in diagnosis of common rheumatologic conditions Understand new developments in the management of common rheumatologic conditions Be familiar with new anti-rheumatic drugs and recognize complications from anti-rheumatic drugs r. Matsos: Rheumatology Update 2017

3 CSIM Annual Meeting 2017 Conflict Disclosures Definition: A Conflict of Interest may occur in situations where the personal and professional interests of individuals may have actual, potential or apparent influence over their judgment and actions. I have the following conflicts to declare: Company/Organization Details Advisory Board or equivalent Speakers bureau member Payment from a commercial organization. (including gifts or other consideration or in kind compensation) Grant(s) or an honorarium Patent for a product referred to or marketed by a commercial organization. Investments in a pharmaceutical organization, medical devices company or communications firm. Participating or participated in a clinical trial Sanofi-Genzyme, Janssen, Astra-Zeneca N/A N/A Sanofi-Genzyme N/A N/A Astra-Zeneca, Celgene, BMS, GSK Speaker Local Principal Investigator

4 CASE 70 year old woman has a new onset left sided headache lasting more than 24 hours unrelieved by OTC Tylenol with ESR of 39 and a CRP of 9. Past Medical history is remarkable for Atrial Fibrillation for which she is currently treated with Coumadin. She denies jaw claudication or vision symptoms. She denies pain affecting the shoulder and pelvic girdle musculature. On examination she has left sided scalp tenderness but no temporal artery tenderness or decreased pulsation. What is her pretest probability of having GCA (temporal arteritis)? 1. Very low 2. Low 3. Moderate 4. High

5 CASE What test would you perform next? 1. None she doesn t have temporal arteritis 2. Carotid Doppler ultrasound of her temporal artery 3. MRI/MRA of her scalp arteries 4. Temporal artery biopsy of her left temporal artery

6 Giant Cell Arteritis Most common systemic vasculitis among North Americans Causes granulomatous inflammation chiefly of the aortic arch and the extracranial portion of the carotid artery. Disease manifests after 50 years of age headache, PMR, jaw claudication, and visual loss Early diagnosis and treatment with prednisone at a daily dose of 40 to 60 mg per day prevents blindness and dramatically ameliorates symptoms. Minority of patients taper off prednisone over 3-6 months, Majority cycles of flares and remissions that result in prednisone therapy over months or years. Alternatives to glucocorticoids have not been reliably effective in randomized, controlled trials. Hellman NEJM 2017; 377:

7 ACR 1990 criteria for the classification of giant cell (temporal) arteritis Must have at least 3 of the 5 criteria present: Age > 50 years at disease onset New headache Temporal artery abnormality (tender or decreased pulse) Elevated Westergren ESR > 50 mm/hr Abnormal artery biopsy: mononuclear cell infiltrate, granulomatous inflammation, usually multinucleated giant cell VCRC Modification: Large Vessel Vasculitis (LVV) by angiogram or biopsy (not explained by alternate diagnosis) Hunder GG, et al.. Arthritis Rheum. 1990;33:

8 Temporal Artery Bx in GCA -Retrospective study of 335 patients who underwent TAB for suspicion of GCA from 2001 to biopsies (24.2%) were positive for GCA Predictors of Positive Biopsy: temporal cutaneous hyperalgesia (OR = 10.8; p < 0.001) jaw claudication (OR = 4.6; p = 0.001) recent-onset headache (OR = 4.4; p = 0.001) decreased temporal pulse (OR = 2.8; p = 0.02) pain and stiffness in neck and shoulders (OR = 2.3; p = 0.05) unintentional weight loss (OR = 1.33; p = 0.003) age (OR = 1.085; p = 0.004) length of the surgical specimen (OR = 1.079; p = 0.028) ESR (OR = 1.042; p < 0.001) González-López JJ et al Acta Ophthalmol.2013 Dec;91(8):763-8.

9 Temporal Artery Biopsies in Patients with Temporal Arteritis Clinical manifestations improve quickly after starting glucocorticoid therapy but vascular inflammation appears to persist. In a population of patients with TA treated with glucocorticoids, repeat biopsies demonstrated evidence of vasculitis at 12 months of treatment (75% of biopsies at 6 months) These findings underscore the utility of temporal artery biopsy even in treated patients. Fritzlen et al Arthritis Rheumatol. 2015; 67 (suppl 10). Maleszewski et al Modern Pathology 2017; 30:

10 Ultrasound for Investigation of Temporal Arteritis Color-duplex ultrasonography can be used to assess vascular inflammation of the superficial temporal and accessible large arteries. A typical ultrasonography finding in GCA is the halo sign, a hypoechoic ring around the arterial lumen representing inflammation induced edematous thickening of the arterial wall

11 Ultrasound for Investigation of Temporal Arteritis US studies in GCA appear heterogeneous due to differences of: Inclusion criteria Technical equipment Vessels scanned Diagnostic references Sensitivity ranged from 55% to 100% Specificity ranged from 78% to 100% in 10 studies (n = 696 patients). Currently no role for ultrasound of temporal arteries as halo sign disappears quickly after steroid treatment, and only reappears during major flare F. Buttgereit, et al JAMA. 2016;315(22):

12 MRI scalp arteries for the diagnosis of GCA In GCA, contrast-enhanced high-resolution MRI can demonstrate arterial wall thickening with mural and periadventitial contrast enhancement. Klink et al Radiology 2014 Aug 6:

13 MRI for the diagnosis of Temporal Arteritis (GCA) Evaluate the Diagnostic accuracy of MRI in comparison with TAB results. Secondary analyses included comparison to clinician diagnosis and ACR criteria.

14 MRI for the diagnosis of Temporal Arteritis (GCA) Results: 191 patients were screened and 171 were included in the study. ACR criteria were met in 137 patients (80.1%). MRI showed abnormal scalp arteries in 60 patients (35.1%) while biopsy was positive in 31 (18.1%). MRI was positive in 29 of those 31 patients with positive TAB (Sensitivity 93.6%). MRI was normal in 109 of those 140 with negative TAB (Specificity 77.9%). Relative to TAB, the negative predictive value of MRI was 98.2%. Conclusion: Negative MRI is highly predictive of a negative TAB, such that patients with a negative MRI could safely be spared TAB. Rhéaume et al Arthritis Rheumatol. 2017: 69(1)

15 Ultrasound: If halo present GCA If not present proceed with algorithm

16 CASE 70 year old woman has a new onset left sided headache lasting more than 24 hours unrelieved by OTC Tylenol with ESR of 39 and a CRP of 9. MRI evaluation demonstrates abnormal scalp arteries, subsequent TA biopsy positive for vasculitis. Prednisone 60mg po daily started with resolution of headache, normalization of inflammatory markers, however during taper of steroids (15mg), GCA symptoms return. Prednisone is increased with resolution of symptoms once again. How would you treat this patient now? 1. Attempt further wean of steroid and hope she doesn t flare again 2. Maintain current effective dose of Prednisone 3. Add steroid sparing DMARD 4. Isn t there a better option?

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18 Trial of Tocilizumab in Giant-Cell Arteritis (GiACTA) Giant-cell arteritis commonly relapses when glucocorticoids are tapered, and the prolonged use of glucocorticoids is associated with side effects. The effect of the interleukin-6 receptor alpha inhibitor tocilizumab on the rates of relapse during glucocorticoid tapering was studied in patients with giant-cell arteritis. 251 patients were randomly assigned in a 2:1:1:1 ratio, to receive: subcutaneous tocilizumab (at a dose of 162 mg) weekly or every other week (combined with a 26-week prednisone taper) or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. Primary outcome: rate of sustained glucocorticoid-free remission at week 52 in each tocilizumab group as compared with the rate in the placebo group that underwent the 26-week prednisone taper. Stone et al. NEJM 2017; 377(4):

19 Trial of Tocilizumab in Giant-Cell Arteritis (GiACTA) RESULTS: Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly 53% of those treated with tocilizumab every other week, 14% of those in the placebo group that underwent the 26-week prednisone taper 18% of those in the placebo group that underwent the 52-week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52-week period was 1862 mg in each tocilizumab group 3296 mg in the placebo group that underwent the 26-week taper (P<0.001 for both comparisons) 3818 mg in the placebo group that underwent the 52-week taper (P<0.001 for both comparisons). Stone et al. NEJM 2017; 377(4):

20 Time to First Flare after Clinical Remission of Giant-Cell Arteritis in All Patients. Stone JH et al. N Engl J Med 2017;377:

21 Trial of Tocilizumab in Giant-Cell Arteritis (GiACTA) CONCLUSIONS Tocilizumab, received weekly or every other week, combined with a 26-week prednisone taper was superior to either 26-week or 52-week prednisone tapering plus placebo with regard to sustained glucocorticoid-free remission in patients with giant-cell arteritis. Longer follow-up is necessary to determine the durability of remission and safety of tocilizumab. FDA fast tracked assessment and Tocilizumab now approved for use in United States Stone et al. NEJM 2017; 377(4):

22 CASE 59 year old woman is diagnosed with Rheumatoid Arthritis after presenting to clinic with 16 week history of an inflammatory polyarthritis with positive Rheumatoid Factor and Anti-CCP Antibodies. Treatment is initiated with Methotrexate monotherapy with persistent disease activity after 12 weeks of treatment. Combination DMARD treatment (Lefluonamide + MTX) is then utilized with active disease after another 12 weeks of treatment. On examination she has 12 swollen joints, 18 tender joints. Her ability to complete ADLs is progressively worsening. Blood work shows elevated CRP. What management would you institute at this time? 1. Start treatment with Prednisone in combination with current DMARD therapy. 2. Initiate treatment with a biologic DMARD in combination with Methotrexate. 3. Initiate treatment with tofacitinib in combination with Methotrexate. 4. I m a traditionalist - Gold injections it is!

23 Biologics for the management of RA Anti-TNFs etanercept, infliximab, adalimumab, golimumab, certolizumab T cell co-stimulatory inhibitor abatacept B lymphocytedepleting agent rituximab IL-6 antagonist tocilizumab sarilumab Bykerk VP, et al. J Rheumatol 2012;39:

24 Biologics for the management of RA B lymphocytedepleting agent rituximab T cell co-stimulatory inhibitor abatacept Anti-TNFs etanercept, infliximab, adalimumab, IL-6 antagonist IL-1 antagonist golimumab, tocilizumab certolizumab anakinra Binds to TNF-α, inhibiting its action 1. Bykerk VP, et al. J Rheumatol 2012;39: Enbrel (Amgen) Product Monograph. September 13, Remicade (Janssen) Product Monograph. August 6, Orecnia (BMS) Product Monograph. October 7, Actemra (Hoffman-La Roche Ltd) Product Monograph. December 5, Kineret (Swedish Orphan BioVitrum AB) Product Monograph. May 28, Rituxan (Hoffman-La Roche) Product Monograph. October 17,

25 Biologics for the management of RA Anti-TNFs etanercept, infliximab, adalimumab, golimumab, certolizumab B lymphocytedepleting agent rituximab T cell co-stimulatory inhibitor abatacept IL-6 antagonist tocilizumab Binds to IL-6 receptor, blocking IL-6 from binding to cell surface receptor IL-1 antagonist anakinra 1. Bykerk VP, et al. J Rheumatol 2012;39: Enbrel (Amgen) Product Monograph. September 13, Remicade (Janssen) Product Monograph. August 6, Orecnia (BMS) Product Monograph. October 7, Actemra (Hoffman-La Roche Ltd) Product Monograph. December 5, Kineret (Swedish Orphan BioVitrum AB) Product Monograph. May 28, Rituxan (Hoffman-La Roche) Product Monograph. October 17,

26 Biologics for the management of RA Anti-TNFs etanercept, infliximab, adalimumab, golimumab, certolizumab B lymphocytedepleting agent rituximab T cell costimulatory inhibitor abatacept Binds to CD80/86 costimulatory molecules on antigen presenting cells, inhibiting IL-6 T-cell antagonist activation tocilizumab IL-1 antagonist anakinra 1. Bykerk VP, et al. J Rheumatol 2012;39: Enbrel (Amgen) Product Monograph. September 13, Remicade (Janssen) Product Monograph. August 6, Orecnia (BMS) Product Monograph. October 7, Actemra (Hoffman-La Roche Ltd) Product Monograph. December 5, Kineret (Swedish Orphan BioVitrum AB) Product Monograph. May 28, Rituxan (Hoffman-La Roche) Product Monograph. October 17,

27 Biologics for the management of RA Anti-TNFs etanercept, infliximab, adalimumab, golimumab, certolizumab T cell co-stimulatory inhibitor abatacept IL-6 antagonist tocilizumab B lymphocyte-depleting agent rituximab Binds to CD20 on B cells, resulting in IL-1 depletion antagonist anakinra 1. Bykerk VP, et al. J Rheumatol 2012;39: Enbrel (Amgen) Product Monograph. September 13, Remicade (Janssen) Product Monograph. August 6, Orecnia (BMS) Product Monograph. October 7, Actemra (Hoffman-La Roche Ltd) Product Monograph. December 5, Kineret (Swedish Orphan BioVitrum AB) Product Monograph. May 28, Rituxan (Hoffman-La Roche) Product Monograph. October 17,

28 Cytokines important to the pathogenesis of RA Cytokines in the pathogenesis of RA Cytokines JAKs IL-2 JAK1/JAK3 IL-4 JAK1/JAK3 Cytokine IL-7 IL-15 JAK1/JAK3 JAK1/JAK3 IL-21 JAK1/JAK3 IL-6 JAK1/JAK2/Tyk2 IFNα and IFNβ JAK1/Tyk2 IFNγ JAK1/JAK2 Cytoplasm JAK JAK IL-10 IL-12 IL-23 JAK1/Tyk2 JAK2/Tyk2 JAK2/Tyk2 IL-1 IL-17 IL-18 TGF-β TNF JAK-independent 1. Shuai K, Liu B. Nat Rev Immunol 2003;3(11): Jiang JK, et al. J Med Chem 2008;51(24): Meyer DM, et al. J Inflamm (Lond) 2010;7:4. 4. Flanagan ME et al. J Med Chem 2010;53:

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31 Gadina et al. Arthritis & Rheumatology 2016; 68 (1): 31-34

32 Efficacy Flesichmann et al Lancet 2017; 390 (10093):

33 Incidence Rates and Adjusted HR of HZ in Tofacitinib and bdmard treated patients with RA Curtis JR et al. Ann Rheum Disease 2016: 75:

34 Vaccination Summary of CRA Recommendations for Vaccination in Patients with RA (Recommendations 7-9) Methotrexate* Leflunomide Sulfasalazine All biologics Influenza (annual) Inactivated/ Killed Vaccines Pneumococcal (booster after 3-5 years) Hepatitis B Live attenuated vaccines Herpes Zoster Other Caution Caution Caution Avoid Avoid Recommended; ideally administer prior to initiating therapy. Recommended in high-risk groups including residents, travelers or close contact with individuals from hepatitis B endemic areas, illicit drug users, persons engaging in risky sexual behaviors/history of STI, men who have sex with men, chronic liver disease, occupational exposures, frequent blood transfusions. Recommended in RA patients > 60 years old. * Methotrexate 25 mg per week. Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi: /jrheum

35 CASE 59 year old woman is diagnosed with Rheumatoid Arthritis after presenting to clinic with 16 week history of an inflammatory polyarthritis with positive Rheumatoid Factor and Anti-CCP Antibodies. Disease remission is achieved with anti-tnf treatment in combination with MTX. 5 years later she begins to complain about left knee pain with worsens with ambulation. There is no associated swelling. No other joint pain is reported. X-rays of the knee demonstrate advanced osteoarthritis. Total Knee Arthroplasty is recommended for management. You assess her in clinic for peri-operative management. How would you manage her rheumatoid arthritis therapy? 1. Discontinue both anti-tnf and Methotrexate treatment 3 ½ lives before surgery and instruct not to restart for at least 6 weeks post-operatively. 2. Discontinue anti-tnf and MTX treatment one ½ life before surgery and not restart for 6 weeks post-operatively 3. Continue Methotrexate but discontinue anti-tnf one ½ life before surgery and restart one month post-operatively 4. No concerns continue both medications throughout surgical process.

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37 2017 ACR Guideline for Perioperative Management of Antirheumatic Medication in Patients with Rheumatic Disease Undergoing Elective THA or TKA Goodman et al. Arthritis Care & Research 2017; 69 (8):

38 2017 ACR Guideline for Perioperative Management of Antirheumatic Medication in Patients with Rheumatic Disease Undergoing Elective THA or TKA Goodman et al. Arthritis Care & Research 2017; 69 (8):

39 Perioperative Care Recommendation 1. Methotrexate can be safely continued in the perioperative period for RA patients undergoing elective orthopedic surgery. 2. Biologics should be held prior to surgical procedures. The timing for withholding therapy should be based on the individual patient, the nature of the surgery, and the pharmacokinetic properties of the agent. Biologic DMARDs may be restarted postoperatively if there is no evidence of infection and wound healing is satisfactory. Level of Evidence I II, IV Strength Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi: /jrheum A C 44

40 Mean half-lives of biologic agents licensed for use in Canada Mean half-life 2 half-lives 5 half-lives (days) (days) (days) Etanercept (ETN) Adalimumab (ADA) Infliximab (IFX) Golimumab (GOL) Certolizumab (CTZ) Rituximab (RTX) Abatacept (ABAT) Tocilizumab (TCZ) Health Canada Drug Product Database (accessed ): Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi: /jrheum

41 Perioperative Management: Joint Replacement Patients with rheumatic disease undergoing TKA, THA at increased risk joint infection Non-Biologic DMARDs can be continued throughout the perioperative period Biologics should be held one dosing cycle prior to OR and restarted 14 days post-op (if evidence of wound healing) Goodman et al. Arthritis Care & Research 2017; 69 (8):